US5650390A - Gonadotropin containing pharmaceutical compositions with sucrose stabilizer - Google Patents
Gonadotropin containing pharmaceutical compositions with sucrose stabilizer Download PDFInfo
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- US5650390A US5650390A US08/244,575 US24457594A US5650390A US 5650390 A US5650390 A US 5650390A US 24457594 A US24457594 A US 24457594A US 5650390 A US5650390 A US 5650390A
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- United States
- Prior art keywords
- sucrose
- solution
- pharmaceutical composition
- fsh
- lactose
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 title claims abstract description 65
- 229930006000 Sucrose Natural products 0.000 title claims abstract description 65
- 239000005720 sucrose Substances 0.000 title claims abstract description 65
- 102000006771 Gonadotropins Human genes 0.000 title claims abstract description 22
- 108010086677 Gonadotropins Proteins 0.000 title claims abstract description 22
- 239000002622 gonadotropin Substances 0.000 title claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- 239000003381 stabilizer Substances 0.000 title description 6
- 239000000203 mixture Substances 0.000 claims abstract description 81
- 238000009472 formulation Methods 0.000 claims abstract description 55
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000004471 Glycine Substances 0.000 claims abstract description 24
- 230000000087 stabilizing effect Effects 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 12
- 239000008247 solid mixture Substances 0.000 claims description 7
- 238000003860 storage Methods 0.000 claims description 6
- 239000011872 intimate mixture Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 5
- 238000001035 drying Methods 0.000 claims 1
- 229940094892 gonadotropins Drugs 0.000 abstract description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 37
- 239000008101 lactose Substances 0.000 description 37
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 31
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 31
- 229940028334 follicle stimulating hormone Drugs 0.000 description 30
- 239000000546 pharmaceutical excipient Substances 0.000 description 20
- 102000009151 Luteinizing Hormone Human genes 0.000 description 19
- 108010073521 Luteinizing Hormone Proteins 0.000 description 19
- 229940040129 luteinizing hormone Drugs 0.000 description 18
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 11
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 11
- 230000015556 catabolic process Effects 0.000 description 10
- 238000006731 degradation reaction Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229940084986 human chorionic gonadotropin Drugs 0.000 description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 7
- 229930195725 Mannitol Natural products 0.000 description 7
- 239000000594 mannitol Substances 0.000 description 7
- 235000010355 mannitol Nutrition 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 238000004108 freeze drying Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000003708 ampul Substances 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 102000009027 Albumins Human genes 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229910021204 NaH2 PO4 Inorganic materials 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 108020004511 Recombinant DNA Proteins 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 102000003390 tumor necrosis factor Human genes 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 2
- 102000018997 Growth Hormone Human genes 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- 229910003944 H3 PO4 Inorganic materials 0.000 description 2
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- ZDRRIRUAESZNIH-BZGUUIOASA-N (2s)-1-[(4r,7s,10s,13s,16s,19r)-19-amino-7-(2-amino-2-oxoethyl)-13-[(2s)-butan-2-yl]-10-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-n-[(2s)-1-[(2-amino-2-oxoethyl)amino]- Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)[C@@H](C)O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZDRRIRUAESZNIH-BZGUUIOASA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108020002230 Pancreatic Ribonuclease Proteins 0.000 description 1
- 102000005891 Pancreatic ribonuclease Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010020661 Profasi Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 108010047196 Urofollitropin Proteins 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical group [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940015047 chorionic gonadotropin Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- -1 lactose and mannitol Chemical class 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 108010070915 orgotein Proteins 0.000 description 1
- 229960004534 orgotein Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- TUGDLVFMIQZYPA-UHFFFAOYSA-N tetracopper;tetrazinc Chemical compound [Cu+2].[Cu+2].[Cu+2].[Cu+2].[Zn+2].[Zn+2].[Zn+2].[Zn+2] TUGDLVFMIQZYPA-UHFFFAOYSA-N 0.000 description 1
- 239000011123 type I (borosilicate glass) Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- FYGDTMLNYKFZSV-BYLHFPJWSA-N β-1,4-galactotrioside Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@H](CO)O[C@@H](O[C@@H]2[C@@H](O[C@@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-BYLHFPJWSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
Definitions
- the present invention concerns gonadotropin containing pharmaceutical compositions. More precisely, it concerns compositions of sucrose-stabilized gonadotropins.
- the gonadotropins of the present invention comprise FSH (Follicle Stimulating Hormone), LH (Luteinizing Hormone) and hCG (Human Chorionic Gonadotropin).
- composition of lyophilised proteins is described in M. J. Pikal, BioPharm, October 1990, 25-30.
- proteins such as growth hormone and ribonuclease A, formulated by using stabilizing excipients such as mannitol, glycin, arginine and lactose.
- the lyophilisation is described of proteins in the presence of various substances in their amorphous state, as sugars, which increase the collapse temperature and possible to obtain shorter lyophilisation times.
- German patent DE 3520228 describes bioactive proteins such as lymphokines, interferons, TNF (Tumor Necrosis Factor), insulin, growth hormone, in formulations which are stabilized by means of polysaccharides comprising repetitive maltotriose units.
- TNF Tumor Necrosis Factor
- insulin growth hormone
- formulations which are stabilized by means of polysaccharides comprising repetitive maltotriose units.
- sucrose as a stabilizing agent is known, for instance, in a formulation of lyophilized orgotein, as described in U.S. Pat. No. 3,637,640.
- patent application WO 89/10407 describes the formulation with sucrose of M-CSF (Macrophage-Colony Stimulating Factor); patent application WO 89/09610 describes, instead, formulations of TNF which have been stabilized with albumin, dextran, polyethylene glycol, 80 polysorbate PVP, lactose, trialose or even sucrose.
- M-CSF Macrophage-Colony Stimulating Factor
- patent application WO 89/09610 describes, instead, formulations of TNF which have been stabilized with albumin, dextran, polyethylene glycol, 80 polysorbate PVP, lactose, trialose or even sucrose.
- the injectable formulations of gonadotropins are obtained by a process which includes their lyophilisation in order to obtain a dry powder.
- Gonadotropins are highly liable to denaturization during the lyophilisation process and it is desirable to obtain stable formulations able to maintain a longer cycle life when they are stored at room temperature.
- European Patent EP 448146 describes lyophilised gonadotropin containing preparations, which are stabilized by means of a dicarboxylic acid salt, as, for instance, citric acid, tartaric acid and aspartic acid.
- Gonadotropins which are found on the market are stabilized by means of saccharides, for instance hCG is stabilized by means of mannitol (Profasi®, SERONO) and FSH is stabilized by means of lactose (Metrodin®, SERONO).
- sucrose confers a better stability to the formulation of gonadotropins and in particular to the form of these glycoproteins which have been prepared by recombinant DNA technique.
- the main object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising a solid intimate mixture of a gonadotropin, such as FSH, LH or hCG, and a stabilizing amount of sucrose, alone or in combination with other stabilizing agents.
- a gonadotropin such as FSH, LH or hCG
- a further object is to provide a process for the preparation of said pharmaceutical composition, the step of lyophilising an aqueous solution of the components.
- Another object is to provide a dosage form of said pharmaceutical composition comprising the said solid mixture hermetically closed in a sterile condition within a container suitable for storage before use and suitable for reconstitution of the mixture for injectable substances.
- Another object is to provide a solution for said solid mixture reconstituted into an injectable solution.
- various formulations of recombinant FSH containing 150 I.U. pro vial have been prepared with various excipients: lactose, sucrose, glycine, sucrose plus glycine, lactose plus albumin and lactose plus glycine. All the formulations have been prepared by dissolving the excipients in phosphate buffer at pH 7, except the formulation with lactose (10 mg) which has been dissolved into H 2 O for injection and adjusted at pH 6.4.
- Tables 1 and 2 give the results of the tests effected on two different hatches of recombinant FSH in the presence of different excipients, after 2 and 4 weeks for batch 1 (Tab. 1) and after 1 and 3 weeks for batch 2 (Tab. 2).
- sucrose i.e. formulations with sucrose alone and with sucrose plus glycine.
- Sucrose shows, surprisingly, to be an efficient stabilizing agent against the denaturization of the gonadotropins.
- the stabilizing agents which are employed in the compositions of the present invention include, therefore, sucrose alone or in combination with other excipients, preferably aminoacids such as glycine.
- the stability has been studied of recombinant FSH and recombinant LH.
- the gonadotropins produced according to the technique of recombinant DNA must be subjected to a high purification process in order to avoid contamination agents having a non-human origin and this high purity renders them less stable than the corresponding urinary gonadotropins.
- the recombinant gonadotropins of the present invention have been prepared by expression in CHO (Chinese Hamster Ovary) cells, transformed with the corresponding recombinant DNA, according to the
- the lyophilisate was prepared by diluting the bulk of gonadotropin with a solution of the excipient in water for injection ("a" formulation) or 0.01M phosphate buffer ("b" and "c” formulations) in order to achieve the concentration of 200 I.U./ml, adjusting the pH at 6.4 for the lactose-containing formulations and at 7 for the sucrose containing or sucrose-plus-glycin-containing formulations.
- the solution has been filtered, brought to the final volume with the remaining solution of the excipient in order to achieve the concentration of 150 I.U./ml and lyophilized.
- the accelerated stability of the FSH formulations has been determined through the biological activity test, performed at the time intervals which are reported in the corresponding Tables.
- the degradation was significant for the lactose containing formulations for all the test temperatures and for all the three batches. On the contrary, no appreciable variation was observed for the sucrose containing formulation of batch 1 at the same temperatures. For the formulation containing sucrose plus glycine relating to the first batch, the only appreciable degradation was observed at 50° C. For the formulations with sucrose or sucrose+glycine of the remaining batches, a degradation is observed which was lower anyway than that of the lactose containing formulation.
- Tab. 5 gives further accelerated stability data, derived by the biological activity data, for 2 different batches (batch 1 and batch 2) of recombinant FSH formulations containing 150 I.U./ml FSH and 30 mg sucrose in 3 ml vials.
- a degradation is calculated of about 20% and 8% respectively for the lactose formulations stored for two
- sucrose containing formulations remain unchanged for two years at 4° C. and a decrease of only 9% is calculated for the same formulations after two years at 25° C.
- sucrose formulation "a”, 30 mg sucrose
- lactose formulation "b”, 10 mg lactose
- mannitol formulation "c”, 20 mg mannitol
- Tab. 10 gives the estimated values derived by the biological assay performed at different times for said hCG formulations stored at a temperature of 55° C.
- sucrose is shown to be the most suited excipient in order to preserve hCG stability, i.e. an excipient which is much better than mannitol and better than lactose, even if, in this case, the stability difference for the three formulations is less strong with respect to the FSH or LH case.
- the pH of the FSH solution and of the residual sucrose solution was adjusted at 7 by means of 0.1M NaOH or H 3 PO 4 .
- the FSH containing solution was filtered through a Durapore 0.22 um sterile filter and brought to the final volume with the residual excipients solution filtered through the same Durapore filter. During the process the solution temperature was kept between 4° and 8° C.
- Sucrose (57.3 g), Na 2 HPO 4 .2H 2 O (0.99 g) and NaH 2 PO 4 .H 2 O (0.62 g) were dissolved into water for injectables (600 ml) in order to obtain the starting sucrose solution.
- the recombinant LH bulk (90,000 I.U.) was diluted with the sucrose solution so that an LH solution is obtained at 300 I.U./ml.
- the pH of the LH solution and of the residual sucrose solution was adjusted at 8 by means of 0.1M NaOH or H 3 PO 4 .
- the LH containing solution was filtered through a 0.22 um Durapore sterile filter and brought to the final volume by means of the residual excipients solution filtered through the same Durapore filter. During the process the solution temperature was kept between 4° and 8° C.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Reproductive Health (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
Pharmaceutical compositions containing FSH, LH or hCG stabilized by means of a combination of sucrose and glycine. The formulation is particularly suitable for stabilizing a lyophilisate of recombinant gonadotropins.
Description
This application is a 371 of PCT/It92/00165, filed Dec. 17, 1992.
The present invention concerns gonadotropin containing pharmaceutical compositions. More precisely, it concerns compositions of sucrose-stabilized gonadotropins. The gonadotropins of the present invention comprise FSH (Follicle Stimulating Hormone), LH (Luteinizing Hormone) and hCG (Human Chorionic Gonadotropin).
It is known that highly purified proteins are time-unstable and are stabilized, for instance, in admixture with saccharides, such as lactose and mannitol, or else with proteins and aminoacids, such as albumin and glycine. Other high-molecular-weight compounds, having a biological origin, as, for instance, the marine colloids, dextran and other polysaccharides and the phospholipids often work equally well. Anyway, since the gonadotropins of the present invention are administered parenterally, these excipients are not suited for an injectable composition because of their allergenicity or their insufficient solubility, in some cases because of their potential toxicity or a concourse of these effects.
The composition of lyophilised proteins is described in M. J. Pikal, BioPharm, October 1990, 25-30. There are reported examples of proteins, such as growth hormone and ribonuclease A, formulated by using stabilizing excipients such as mannitol, glycin, arginine and lactose.
In particular, the lyophilisation is described of proteins in the presence of various substances in their amorphous state, as sugars, which increase the collapse temperature and possible to obtain shorter lyophilisation times. However, it is not feasible, according to the author, to foresee a standard formulation for all the proteins, and the choice of the best formulation requires a remarkable selection work.
German patent DE 3520228 describes bioactive proteins such as lymphokines, interferons, TNF (Tumor Necrosis Factor), insulin, growth hormone, in formulations which are stabilized by means of polysaccharides comprising repetitive maltotriose units. The use of sucrose as a stabilizing agent is known, for instance, in a formulation of lyophilized orgotein, as described in U.S. Pat. No. 3,637,640. International patent application WO 89/10407 describes the formulation with sucrose of M-CSF (Macrophage-Colony Stimulating Factor); patent application WO 89/09610 describes, instead, formulations of TNF which have been stabilized with albumin, dextran, polyethylene glycol, 80 polysorbate PVP, lactose, trialose or even sucrose.
The injectable formulations of gonadotropins are obtained by a process which includes their lyophilisation in order to obtain a dry powder. Gonadotropins are highly liable to denaturization during the lyophilisation process and it is desirable to obtain stable formulations able to maintain a longer cycle life when they are stored at room temperature.
European Patent EP 448146 describes lyophilised gonadotropin containing preparations, which are stabilized by means of a dicarboxylic acid salt, as, for instance, citric acid, tartaric acid and aspartic acid. Gonadotropins which are found on the market are stabilized by means of saccharides, for instance hCG is stabilized by means of mannitol (Profasi®, SERONO) and FSH is stabilized by means of lactose (Metrodin®, SERONO).
We have now found that sucrose confers a better stability to the formulation of gonadotropins and in particular to the form of these glycoproteins which have been prepared by recombinant DNA technique.
The main object of the present invention is to provide a pharmaceutical composition comprising a solid intimate mixture of a gonadotropin, such as FSH, LH or hCG, and a stabilizing amount of sucrose, alone or in combination with other stabilizing agents.
A further object is to provide a process for the preparation of said pharmaceutical composition, the step of lyophilising an aqueous solution of the components. Another object is to provide a dosage form of said pharmaceutical composition comprising the said solid mixture hermetically closed in a sterile condition within a container suitable for storage before use and suitable for reconstitution of the mixture for injectable substances.
Another object is to provide a solution for said solid mixture reconstituted into an injectable solution. In order to evaluate the excipient's effect on the stability of the active ingredients, various formulations of recombinant FSH containing 150 I.U. pro vial have been prepared with various excipients: lactose, sucrose, glycine, sucrose plus glycine, lactose plus albumin and lactose plus glycine. All the formulations have been prepared by dissolving the excipients in phosphate buffer at pH 7, except the formulation with lactose (10 mg) which has been dissolved into H2 O for injection and adjusted at pH 6.4.
The samples have been stored at 45° C. and tested with a biological assay at fixed intervals of time. Tables 1 and 2 give the results of the tests effected on two different hatches of recombinant FSH in the presence of different excipients, after 2 and 4 weeks for batch 1 (Tab. 1) and after 1 and 3 weeks for batch 2 (Tab. 2).
The biological tests have been performed in compliance with the regulations of the European Pharmacopceia and effected in duplicate. The tests for FSH and LH are reported in the "Menotropin" monography, whereas the test for hCG is reported in the "Chorionic Gonadotropin" monography.
The results show that the most stable formulations among those tested are those containing sucrose, i.e. formulations with sucrose alone and with sucrose plus glycine. Sucrose shows, surprisingly, to be an efficient stabilizing agent against the denaturization of the gonadotropins.
The stabilizing agents which are employed in the compositions of the present invention include, therefore, sucrose alone or in combination with other excipients, preferably aminoacids such as glycine. In particular, the stability has been studied of recombinant FSH and recombinant LH.
The gonadotropins produced according to the technique of recombinant DNA must be subjected to a high purification process in order to avoid contamination agents having a non-human origin and this high purity renders them less stable than the corresponding urinary gonadotropins.
The recombinant gonadotropins of the present invention have been prepared by expression in CHO (Chinese Hamster Ovary) cells, transformed with the corresponding recombinant DNA, according to the
TABLE 1
______________________________________
Batch 1 of recombinant FSH I.U.
Amount Theoretical 45° C.
45° C.
Excipient (mg) titer T = 0 2 weeks
4 weeks
______________________________________
Lactose 10 167.31 129.0 139.0 104.0
Lactose 30 167.31 132.0 118.0 116.0
Sucrose 30 167.31 158.0 163.0 136.0
Sucrose 50 167.31 140.0 135.0 150.0*
Sucrose + Glycine
20 + 10 167.31 144.0 143.0 186.0
Lactose + Albumin
20 + 3 167.31 127.0*
134.0 128.0
Glycine 20 167.31 132.0 107.0 --
Lactose + Glycine
20 + 10 167.31 153.0 132.0 104.0
______________________________________
*valid only one assay
TABLE 2
______________________________________
Batch 2 of recombinant FSH 150 I.U.
Amount Theoretical 45° C.
45° C.
Excipient (mg) titer T = 0 1 week
4 weeks
______________________________________
Lactose 10 155.08 163.0 121.0 103.0
Lactose 30 155.08 164.0 166.0 108.0
Sucrose 30 155.08 165.0 128.0 151.0
Sucrose 50 155.08 150.0 143.0 157.0
Sucrose + Glycine
20 + 10 155.08 160.0 152.0 185.0
Lactose + Glycine
20 + 3 155.08 172.0 136.0 101.0
Glycine 20 155.08 136.0 115.0*
97.0*
Lactose + Albunin
20 + 10 155.08 171.0*
137.0 157.0
______________________________________
*valid only one assay
technique described in European patents EP 160699 and EP 211894.
The close study of recombinant-FSH-containing formulations has been performed by using different compositions, according to the lay-out of Tab. 3, respectively comprising: a) lactose, b) sucrose, c) sucrose plus glycine.
The lyophilisate was prepared by diluting the bulk of gonadotropin with a solution of the excipient in water for injection ("a" formulation) or 0.01M phosphate buffer ("b" and "c" formulations) in order to achieve the concentration of 200 I.U./ml, adjusting the pH at 6.4 for the lactose-containing formulations and at 7 for the sucrose containing or sucrose-plus-glycin-containing formulations. The solution has been filtered, brought to the final volume with the remaining solution of the excipient in order to achieve the concentration of 150 I.U./ml and lyophilized.
The accelerated stability of these formulations has been studied so that the stability of the same can be foreseen when they are stored in containers at room temperature, through the extrapolation of the data obtained at higher temperatures (+37° C.; +45° C.; +50° C.).
The accelerated stability of the FSH formulations has been determined through the biological activity test, performed at the time intervals which are reported in the corresponding Tables.
Two ampoule preparations of HMG (Menotropin) were used as standard solutions, the first having a biopotency of 101.3 I.U. FSH/ampoule and 85.6 I.U. LH/ampoule, the second having a biopotency of 103.1 I.U. FSH/ampoule and 82.3 I.U. LH/ampoule. The samples, at
TABLE 3
______________________________________
Formulations of recombinant FSH
Dosi- Lac- Gly-
Compo-
metry tose Sucrose
cine Na.sub.2 HPO.sub.4.2H.sub.2 O
NaH.sub.2 PO.sub.4.H.sub.2 O
sition
I.U. mg mg mg mg mg
______________________________________
a 150 10 -- -- -- --
b 150 -- 30 -- 1.11 0.45
c 150 -- 20 10 1.11 0.45
______________________________________
the concentrations 0.5; 1.0 and 2.0 I.U./ml, as well as the standard HMG solutions, were administered to three different groups of five rats each, through subcutaneous injection of 0.5 ml/rat twice a day for three consecutive days (final doses: 1.5; 3.0; 6.0 I.U. FSH/rat). Each animal further received altogether a dose of 40 I.U. hCG.
Data reported in Tab. 4 refer to formulations of 3 different batches of recombinant FSH, containing 150 I.U./ml FSH, in the presence of 10 mg lactose (Composition a), 30 mg sucrose (Composition b) and 20 mg sucrose plus 10 mg glycine (Composition c) in 5 ml vials. The tests were performed at the temperatures 37° C. 45° C. and 50° C.
The degradation was significant for the lactose containing formulations for all the test temperatures and for all the three batches. On the contrary, no appreciable variation was observed for the sucrose containing formulation of batch 1 at the same temperatures. For the formulation containing sucrose plus glycine relating to the first batch, the only appreciable degradation was observed at 50° C. For the formulations with sucrose or sucrose+glycine of the remaining batches, a degradation is observed which was lower anyway than that of the lactose containing formulation.
Tab. 5 gives further accelerated stability data, derived by the biological activity data, for 2 different batches (batch 1 and batch 2) of recombinant FSH formulations containing 150 I.U./ml FSH and 30 mg sucrose in 3 ml vials.
The study was performed on vials stored for 5 weeks at the temperature of 50° C. or for 10 weeks at the
TABLE 4
__________________________________________________________________________
Study of the accelerated stability of recombinant FSH formulation
(3 different batches - Batch 1, Batch 2 and Batch 3 containing 150
I.U./ml FSH) with lactose 10 mg (Composition a), sucrose 30 mg
(Composition b) and sucrose (20 mg) + glycine (10 mg) (Composition
c) in 5 ml vials.
__________________________________________________________________________
Batch 1
50° C. 45° C. 37° C.
T = 0
1 W
3 W 5 W
2 W 4 W
8 W
10 W
11 W
3 W 5 W 9 W
12 W
__________________________________________________________________________
a 147
126
124*
83
163*
84
105
109
-- 140*
109 97
122*
b 156
154
155 151
154 119
115
-- 164
165 165 168
151
c 160
179
143 114
160 134
133
148
-- 136 156*
132
175
__________________________________________________________________________
Batch 2
50° C. 45° C. 37° C.
T = 0
1 W 2 W 5 W 2 W 6 W 8 W 10 W
5 W
7 W
10 W
12 W
__________________________________________________________________________
a 135
50*
40*
-- 96*
51 43 -- 134
108
104
90
b 112
152*
134 96 125 94 89 101
157
163
135
114*
c 145
173*
124 118 143 145 154 135
146
154
139
141
__________________________________________________________________________
Batch 3
50° C. 45° C. 37° C.
T = 0
1 W 3 W 5 W 2 W 4 W 8 W 10 W
3 W
5 W
9 W
12 W
__________________________________________________________________________
a 144
40*
30*
-- 135 30*
20*
-- 106
70
34
--
b 152
136 138 110 161 136 106 110
165
179
159
140
c 135
140 176 125 163 142 122 125
151
151
158
176
__________________________________________________________________________
W = weeks
* = only one assay valid
TABLE 5
__________________________________________________________________________
Study of the accelerated Stability of recombinant FSH
formulations (105 I.U.) with sucrose (30 mg) in 3 ml vials
50° C.
45° C. 37° C.
T= 0
1 W
2 W
3 W
5 W 2 W 4 W 8 W
10 W
3 W
5 W
9 W
12 W
__________________________________________________________________________
Batch 1
141
135
113
136
140 *135
*149
179
166 147
145
149
122
Batch 2
152
144
126
132
*146
135 167 160
162*
154
146
152
175
__________________________________________________________________________
W = Weeks
*only one assay valid
temperature of 45° C. or for 12 weeks at the temperature of 37° C. Again, no activity variation was observed at all the test temperatures for both batches.
The stability forecast at room temperature, given in Tab. 6 and extrapolated from the accelerated stability data of Tab. 5 according to the Garret's method (Garret E. R., J. Pharm. Sci., 51:811, 1962) shows a degradation of about 35% and 80% after two years of storage at 4° C. and 25° C. respectively for the lactose containing formulations.
No degradation is foreseen at 4° C. for the formulations with sucrose or sucrose plus glycine, whereas only a 6% decrease is foreseen for the sucrose containing formulations after two years at 25° C.
The stability has been studied of recombinant LH formulations (75 I.U.) with 50 mg sucrose (Composition a) and 50 mg lactose (Composition b). The exact composition of recombinant LH formulations is given in Table 7.
The study of the accelerated stability of such formulations stored at 37° C., 45° C. and 50° C., determined through the biological activity test measured in I.U. (Table 8) shows what has been already observed for the FSH formulations: the degradation of the sucrose containing preparations was extremely low, whereas the degradation of the lactose containing formulations was more evident.
The stability forecast at room temperature stability extrapolated from the accelerated stability data of Table 8 according to the Garret's method (Garret E. R., J. Pharm. Sci., 51:811, 1962) is given in Table 9.
A degradation is calculated of about 20% and 8% respectively for the lactose formulations stored for two
TABLE 6
______________________________________
Stability forecast of recombinant FSH formulations
(150 I.U.) at room temperature
Activity recovery (%)
4° C.
25° C.
Composition
Excipient 1 year 2 years
1 year
2 years
______________________________________
a Lactose 79.30% 62.89%
41.57%
17.28%
b Sucrose 99.61% 99.22%
96.86%
93.82%
c Sucrose + Glycine
no degradation
no degradation
______________________________________
TABLE 7
______________________________________
Composition of recombinant LH formulations
(75 I.U.) with sucrose 50 mg (Composition a)
and lactose 50 mg (Composition b) in 3 ml vials
Amount
Composition Excipient (mg)
______________________________________
a Sucrose 47.75
NaH.sub.2 PO.sub.4.H.sub.2 O
0.052
Na.sub.2 HPO.sub.4.2H.sub.2 O
0.825
b Lactose 50.00
NaH.sub.2 PO.sub.4.H.sub.2 O
0.052
Na.sub.2 HPO.sub.4.2H.sub.2 O
0.825
______________________________________
TABLE 8
______________________________________
Study of the accelerated stability of recombinant LH
formulation (75 I.U.) in 3 ml vials
______________________________________
Excipient 50° C.
mg T = 0 1 W 2 W 5 W
______________________________________
Sucrose 71 67* 55 59
47.75 (58-86) (34-121) (42-73)
(47-76)
Lactose 77 57* 34* 40
50 (64-93) (37-81) (15-56)
(32-50)
______________________________________
Ex-
cipient
45° C. 37° C.
mg 2 W 5 W 8 W 12 W 6 W 9 W 12 W
______________________________________
Sucrose
65 -- 59 57 67* 70* 72
47,75 (50- (47-73)
(44-75)
(51-86)
(51-96)
(55-94)
85)
Lactose
39 50* 36* -- 44* 42* 48
50 (29- (33-79) (20-57) (32-60)
(31-56)
(38-62)
52)
______________________________________
*Only one assay valid
(In brackets the confidential limits)
W = weeks
TABLE 9
______________________________________
Stability forecast of recombinant LH
formulations (75 I.U.) at room temperature
Activity recovery %
after 2 years
Compositions
Excipient 4° C. 25° C.
______________________________________
a Sucrose 99.68% 90.65%
b Lactose 80.56% 19.86%
______________________________________
years at 4° C. and 25° C. The sucrose containing formulations remain unchanged for two years at 4° C. and a decrease of only 9% is calculated for the same formulations after two years at 25° C.
A study was also performed on urinary hCG formulations by using sucrose (formulation "a", 30 mg sucrose), lactose (formulation "b", 10 mg lactose) or mannitol (formulation "c", 20 mg mannitol) as stabilizers in 3 ml vials containing 500 I.U./vial hCG.
Tab. 10 gives the estimated values derived by the biological assay performed at different times for said hCG formulations stored at a temperature of 55° C.
Once again, sucrose is shown to be the most suited excipient in order to preserve hCG stability, i.e. an excipient which is much better than mannitol and better than lactose, even if, in this case, the stability difference for the three formulations is less strong with respect to the FSH or LH case.
Materials: extra pure sucrose Ph Eur, BP, PH Nord, NF (Merck); lactose RPE ACS (Carlo Erba); glycine for analysis use (Merck), NA2 HPO4.2H2 O for analysis use (Merck), NaH2 PO4.H2 O RPE (Carlo Erba); 85% phosphoric acid RPE ACS (Carlo Erba); 0.1M NaOH (Merck); water for injectables.
As containers, 3 or 5 ml glass vials were used (type I borosilicate glass) with rubber fastener (Fradagrada Pettenati and Pharmagummi, butyl mixture) and aluminum ring.
Sucrose (36 g) Na2 HPO4.2H2 O (1.33 g) and NaH2 PO4.H2 O (0.54 g) were dissolved into water for
TABLE 10
______________________________________
Study of stability at 55° C. of hCG formulations
(500 I.U.) with sucrose (a), lactose (b) and mannitol (c)
Composition
T = 0 3 W 6 W
______________________________________
a 511 567 597
(390.1-670.2)
(407.0-788.7)
(452.2-789.4)
b 534 355 428
(396.7-719.6)
(293.7-430.2)
(330.2-55501)
c 449 332 244
(330.2-611.7)
(259.0-425.5)
(201.8-295.9)
______________________________________
W = weeks (Between brackets confidential 95% limits)
injectables (1,200 ml) in order to obtain the starting sucrose solution. The bulk of recombinant FSH (180,000 I.U.) was diluted with the solution so that an FSH solution was obtained at 200 I.U./ml.
The pH of the FSH solution and of the residual sucrose solution was adjusted at 7 by means of 0.1M NaOH or H3 PO4. The FSH containing solution was filtered through a Durapore 0.22 um sterile filter and brought to the final volume with the residual excipients solution filtered through the same Durapore filter. During the process the solution temperature was kept between 4° and 8° C.
Sucrose (57.3 g), Na2 HPO4.2H2 O (0.99 g) and NaH2 PO4.H2 O (0.62 g) were dissolved into water for injectables (600 ml) in order to obtain the starting sucrose solution. The recombinant LH bulk (90,000 I.U.) was diluted with the sucrose solution so that an LH solution is obtained at 300 I.U./ml.
The pH of the LH solution and of the residual sucrose solution was adjusted at 8 by means of 0.1M NaOH or H3 PO4. The LH containing solution was filtered through a 0.22 um Durapore sterile filter and brought to the final volume by means of the residual excipients solution filtered through the same Durapore filter. During the process the solution temperature was kept between 4° and 8° C.
The solutions containing different excipients were prepared in a similar manner.
3 ml or 5 ml vials were filled with 1 ml of FSH solution or 0.5 ml of LH solution, transferred to the freeze-dryer and cooled at -45° C. for 6 hrs. at least. The lyophilisation was started at the temperature of -45° C. with a 0.07 vacuum. The heating was performed according to the following scheme: +20° C. for 20 hrs., then ±35° C. until the end of the cycle.
On the reconstituted solution the usual quality controls were performed. Although the present invention has been illustrated by means of specific examples, it is understood that variations can be introduced without departing from the spirit and scope of the invention.
Claims (16)
1. A pharmaceutical composition comprising a solid intimate mixture of gonadotropin and a stabilizing amount of sucrose in combination with glycine.
2. A pharmaceutical composition according to claim 1 wherein the sucrose is between 20 and 50 mg per unit dosage.
3. A pharmaceutical composition according to claim 1, wherein the solid intimate mixture is a lyophilisate.
4. A pharmaceutical composition according to claim 3, wherein the gonadotropin is FSH, or LH or hCG.
5. A pharmaceutical composition according to claim 1, wherein the gonadotropin is recombinant.
6. A pharmaceutical composition according to claim 1, containing 75 or 150 I.U. of FSH, 30 mg of sucrose, and an effective amount of glycine.
7. A pharmaceutical composition according to claim 1, containing 75 or 150 I.U. of LH, 47.75 mg of sucrose, and an effective amount of glycine.
8. A pharmaceutical composition according to claim 4, wherein the gonadotropin is recombinant.
9. A process for preparing a pharmaceutical composition according to claim 1 comprising preparing an aqueous solution of the components, distributing the components within containers, and drying or lyophilizing the solution within the containers.
10. A process according to claim 9, wherein the pH of the solution is within the range 6.5-8.5.
11. A process according to claim 10, wherein the pH of the solution is 7 for the FSH formulation and 8 for the LH formulation.
12. Forms of presentation of said pharmaceutical composition consisting essentially of the solid mixture according to claim 1, hermetically closed in a sterile condition in a container suited for storage before use and reconstitution of the mixture in a solvent or a solution for injectables.
13. A solution comprising the solid mixture according to claim 12, reconstituted in a solvent or a solution for injectables.
14. Forms of presentation of said pharmaceutical composition comprising the solid mixture according to claim 8, hermetically closed in a sterile condition in a container suited for storage before use and reconstitution of the mixture in a solvent or a solution for injectables.
15. Forms of presentation of said pharmaceutical composition comprising the solid mixture according to claim 1, hermetically closed in a sterile condition in a container suited for storage before use and reconstitution of the mixture in a solvent or a solution for injectables.
16. Forms of presentation of said pharmaceutical composition comprising the solid mixture according to claim 1, hermetically closed in a sterile condition in a container suited for storage before use and reconstitution of the mixture in a solvent or a solution for injectables, wherein the gonadotropin is FSH, LH or hCG.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITRM910952A IT1250075B (en) | 1991-12-18 | 1991-12-18 | PHARMACEUTICAL COMPOSITIONS CONTAINING GONADOTROPINE. |
| ITRM91A0952 | 1991-12-18 | ||
| PCT/IT1992/000165 WO1993011788A1 (en) | 1991-12-18 | 1992-12-17 | Gonadotropin containing pharmaceutical compositions with sucrose stabilizer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US5650390A true US5650390A (en) | 1997-07-22 |
Family
ID=11400511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US08/244,575 Expired - Lifetime US5650390A (en) | 1991-12-18 | 1992-12-17 | Gonadotropin containing pharmaceutical compositions with sucrose stabilizer |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5650390A (en) |
| EP (1) | EP0618808B1 (en) |
| JP (1) | JP3702313B2 (en) |
| AT (1) | ATE189608T1 (en) |
| AU (1) | AU677773B2 (en) |
| CA (1) | CA2124801C (en) |
| DE (1) | DE69230672T2 (en) |
| DK (1) | DK0618808T3 (en) |
| ES (1) | ES2142860T3 (en) |
| GR (1) | GR3033276T3 (en) |
| IT (1) | IT1250075B (en) |
| PT (1) | PT618808E (en) |
| WO (1) | WO1993011788A1 (en) |
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Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3637640A (en) * | 1970-05-04 | 1972-01-25 | Diagnostic Data Inc | Orgotein stabilized with saccharide process and products |
| US3816617A (en) * | 1972-07-25 | 1974-06-11 | American Home Prod | Method for inducing menses |
| DD141996A1 (en) * | 1979-02-21 | 1980-06-04 | Ingrid Wolf | METHOD FOR PRODUCING LYOPHILIZED LHRH PRAEPARATIONS |
| JPS59109862A (en) * | 1982-12-15 | 1984-06-25 | Takeda Chem Ind Ltd | Preparation of freeze-dried sensitization blood corpuscle |
| WO1985001959A1 (en) * | 1983-11-02 | 1985-05-09 | Integrated Genetics, Inc. | Production of heterodimeric human fertlity hormones |
| DE3520228A1 (en) * | 1984-06-06 | 1985-12-12 | Hayashibara Biochem Lab | WATER-SOLUBLE BIOACTIVE DRY SOLIDS COMPOSITION, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME |
| WO1988010270A1 (en) * | 1987-06-26 | 1988-12-29 | Istituto Di Ricerca Cesare Serono Spa | Urinary follicle stimulating hormone |
| WO1989009610A1 (en) * | 1988-04-13 | 1989-10-19 | Cetus Corporation | Tumor necrosis factor formulations |
| WO1989010407A1 (en) * | 1988-04-29 | 1989-11-02 | Genetics Institute, Inc. | Homogeneous dimeric m-csf and storage stable formulations thereof |
| JPH02121933A (en) * | 1988-10-28 | 1990-05-09 | Kagaku Shiryo Kenkyusho:Kk | Oily hormonal granule for animal |
| EP0388223A2 (en) * | 1989-03-17 | 1990-09-19 | Applied Research Systems ARS Holding N.V. | Novel method of ovulation induction in humans |
| EP0448146A1 (en) * | 1990-03-20 | 1991-09-25 | Akzo Nobel N.V. | Stabilized gonadotropin containing preparations |
-
1991
- 1991-12-18 IT ITRM910952A patent/IT1250075B/en active IP Right Grant
-
1992
- 1992-12-17 US US08/244,575 patent/US5650390A/en not_active Expired - Lifetime
- 1992-12-17 JP JP51077493A patent/JP3702313B2/en not_active Expired - Lifetime
- 1992-12-17 DE DE69230672T patent/DE69230672T2/en not_active Expired - Lifetime
- 1992-12-17 EP EP93901557A patent/EP0618808B1/en not_active Expired - Lifetime
- 1992-12-17 PT PT93901557T patent/PT618808E/en unknown
- 1992-12-17 AT AT93901557T patent/ATE189608T1/en active
- 1992-12-17 WO PCT/IT1992/000165 patent/WO1993011788A1/en active IP Right Grant
- 1992-12-17 CA CA002124801A patent/CA2124801C/en not_active Expired - Lifetime
- 1992-12-17 DK DK93901557T patent/DK0618808T3/en active
- 1992-12-17 ES ES93901557T patent/ES2142860T3/en not_active Expired - Lifetime
- 1992-12-17 AU AU32662/93A patent/AU677773B2/en not_active Expired
-
2000
- 2000-04-19 GR GR20000400959T patent/GR3033276T3/en unknown
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3637640A (en) * | 1970-05-04 | 1972-01-25 | Diagnostic Data Inc | Orgotein stabilized with saccharide process and products |
| US3816617A (en) * | 1972-07-25 | 1974-06-11 | American Home Prod | Method for inducing menses |
| DD141996A1 (en) * | 1979-02-21 | 1980-06-04 | Ingrid Wolf | METHOD FOR PRODUCING LYOPHILIZED LHRH PRAEPARATIONS |
| JPS59109862A (en) * | 1982-12-15 | 1984-06-25 | Takeda Chem Ind Ltd | Preparation of freeze-dried sensitization blood corpuscle |
| WO1985001959A1 (en) * | 1983-11-02 | 1985-05-09 | Integrated Genetics, Inc. | Production of heterodimeric human fertlity hormones |
| DE3520228A1 (en) * | 1984-06-06 | 1985-12-12 | Hayashibara Biochem Lab | WATER-SOLUBLE BIOACTIVE DRY SOLIDS COMPOSITION, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME |
| WO1988010270A1 (en) * | 1987-06-26 | 1988-12-29 | Istituto Di Ricerca Cesare Serono Spa | Urinary follicle stimulating hormone |
| US5128453A (en) * | 1987-06-26 | 1992-07-07 | Istituto Diricerca Cesare Serono Spa | Urinary follicle stimulating hormone |
| WO1989009610A1 (en) * | 1988-04-13 | 1989-10-19 | Cetus Corporation | Tumor necrosis factor formulations |
| WO1989010407A1 (en) * | 1988-04-29 | 1989-11-02 | Genetics Institute, Inc. | Homogeneous dimeric m-csf and storage stable formulations thereof |
| JPH02121933A (en) * | 1988-10-28 | 1990-05-09 | Kagaku Shiryo Kenkyusho:Kk | Oily hormonal granule for animal |
| EP0388223A2 (en) * | 1989-03-17 | 1990-09-19 | Applied Research Systems ARS Holding N.V. | Novel method of ovulation induction in humans |
| EP0448146A1 (en) * | 1990-03-20 | 1991-09-25 | Akzo Nobel N.V. | Stabilized gonadotropin containing preparations |
Non-Patent Citations (4)
| Title |
|---|
| Section Ch., Week 8036, Derwent Publications Ltd., London, GB; Class B04, AN 80 623660 & DD, A 141 996 (Wolf I) 5 Jun. 1980 (abstract). * |
| Section Ch., Week 8036, Derwent Publications Ltd., London, GB; Class B04, AN 80-623660 & DD, A 141 996 (Wolf I) 5 Jun. 1980 (abstract). |
| Section Ch., Week 9025, Derwent Publications Ltd., London, GB; Class B04, AN 90 188387 & JP, A, 2 121 933 (Kagaku Shiryo Kenky) 9 May 1990 (abstract). * |
| Section Ch., Week 9025, Derwent Publications Ltd., London, GB; Class B04, AN 90-188387 & JP, A, 2 121 933 (Kagaku Shiryo Kenky) 9 May 1990 (abstract). |
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| US6319504B1 (en) | 1996-06-24 | 2001-11-20 | University Of Maryland Biotechnology Institute | Treatment and prevention of HIV infection by administration of derivatives of human chorionic gonadotropin |
| US6699656B2 (en) | 1996-06-24 | 2004-03-02 | University Of Maryland Biotechnology Institute | Treatment and prevention of HIV infection by administration of derivatives of human chorionic gonadotropin |
| US5929028A (en) * | 1997-01-15 | 1999-07-27 | Akzo Nobel, N.V. | Liquid gonadotropin containing formulations |
| WO1998051556A1 (en) * | 1997-05-15 | 1998-11-19 | Harris Corporation | Automatic train control system and method |
| US7563763B2 (en) | 1998-07-23 | 2009-07-21 | Ares Trading S.A. | FSH and FSH variant formulations, products and methods |
| US7446090B2 (en) | 1998-07-23 | 2008-11-04 | Ares Trading S.A. | FSH formulation |
| US20080051329A1 (en) * | 1998-07-23 | 2008-02-28 | James Arthur Hoffmann | FSH and FSH variant formulations, products and methods |
| US20060241047A1 (en) * | 1998-07-23 | 2006-10-26 | Hoffmann James A | FSH formulation |
| US7112341B1 (en) | 1999-04-13 | 2006-09-26 | Nektar Therapeutics | Pulmonary administration of dry powder formulations for treating infertility |
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| KR100925017B1 (en) * | 2001-09-07 | 2009-11-03 | 임페리얼 이노베이션스 리미티드 | Oxyntomodulin for preventing or treating excess weight |
| AU2002331939B2 (en) * | 2001-09-12 | 2007-10-25 | Merck Serono Sa | Use of LH in controlled ovarian hyperstimulation |
| US20050049199A1 (en) * | 2001-09-12 | 2005-03-03 | Applied Research Systems Ars Holding N. V. | Use of lh in controlled ovarian hyperstimulation |
| WO2003022301A2 (en) * | 2001-09-12 | 2003-03-20 | Applied Research Systems Ars Holding N.V. | Use of lh in controlled ovarian hyperstimulation |
| EA009210B1 (en) * | 2001-09-12 | 2007-12-28 | Апплайд Резеч Системз Арс Холдинг Н.В. | Use of ln in controlled ovarian huperstimulation |
| WO2003022301A3 (en) * | 2001-09-12 | 2003-04-17 | Applied Research Systems | Use of lh in controlled ovarian hyperstimulation |
| US7341989B2 (en) | 2001-09-12 | 2008-03-11 | Laboratories Seronosa | Use of LH in controlled ovarian hyperstimulation |
| US20040028733A1 (en) * | 2002-02-08 | 2004-02-12 | Alkermes Controlled Therapeutics, Inc. | Polymer-based compositions for sustained release |
| EP1471891A4 (en) * | 2002-02-08 | 2007-04-11 | Alkermes Inc | POLYMER-BASED COMPOSITIONS FOR PROLONGED RELEASE |
| EP1471891A2 (en) * | 2002-02-08 | 2004-11-03 | Alkermes Controlled Therapeutics, Inc. | Polymer-based compositions for sustained release |
| AU2004226666B2 (en) * | 2003-04-02 | 2009-09-03 | Ares Trading S.A. | Liquid pharmaceutical formulations of FSH and LH together with a non-ionic surfactant |
| WO2004087213A1 (en) * | 2003-04-02 | 2004-10-14 | Ares Trading S.A. | Liquid pharmaceutical formulations of fsh and lh together with a non-ionic surfactant |
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| AU2004226666B9 (en) * | 2003-04-02 | 2010-04-08 | Ares Trading S.A. | Liquid pharmaceutical formulations of FSH and LH together with a non-ionic surfactant |
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| US20070059252A1 (en) * | 2003-06-20 | 2007-03-15 | Ares Trading S.A. | Freeze-dried fsh/lh formulations |
| US7740884B2 (en) | 2003-06-20 | 2010-06-22 | Ares Trading S.A. | Freeze-dried FSH/LH formulations |
| US20110201554A1 (en) * | 2005-09-27 | 2011-08-18 | Lg Life Sciences, Ltd. | Hfsh aqueous formulation |
| CN102100908A (en) * | 2009-12-22 | 2011-06-22 | 上海天伟生物制药有限公司 | Protein composition |
| CN102100908B (en) * | 2009-12-22 | 2013-05-08 | 上海天伟生物制药有限公司 | Protein composition |
| KR101483165B1 (en) * | 2009-12-22 | 2015-01-15 | 샹하이 테크웰 바이오파마슈티컬 컴퍼니, 리미티드 | Compositions of menopausal gonadotrophins |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07507047A (en) | 1995-08-03 |
| JP3702313B2 (en) | 2005-10-05 |
| DK0618808T3 (en) | 2000-05-15 |
| CA2124801C (en) | 2007-08-07 |
| ITRM910952A1 (en) | 1993-06-18 |
| DE69230672D1 (en) | 2000-03-16 |
| EP0618808A1 (en) | 1994-10-12 |
| DE69230672T2 (en) | 2000-09-21 |
| CA2124801A1 (en) | 1993-06-24 |
| IT1250075B (en) | 1995-03-30 |
| ATE189608T1 (en) | 2000-02-15 |
| AU677773B2 (en) | 1997-05-08 |
| ES2142860T3 (en) | 2000-05-01 |
| WO1993011788A1 (en) | 1993-06-24 |
| GR3033276T3 (en) | 2000-09-29 |
| AU3266293A (en) | 1993-07-19 |
| EP0618808B1 (en) | 2000-02-09 |
| ITRM910952A0 (en) | 1991-12-18 |
| PT618808E (en) | 2000-07-31 |
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